The risk of development of osteoporosis depends upon peak bone mass achieved and subsequent age-related and particularly postmenopausal bone loss. Inherited factors strongly modify peak bone mass and may influence sensitivity to environmental and life style factors. However it has not been clear how genetic factors operate. Collagen gene defects have been proposed, however our recent data have shown that genetic factors predict indices of bone turnover. Therefore we have taken the approach that differences in regulatory rather than structural pathways may be central to determination of bone mass. Or expressed in molecular terms that variations in specific trans-acting factors, which regulate that action of many target genes in bone, are inherently likely to result in widespread coordinated variations in bone structure and function. This hypothesis is supported by our recent finding that the strong genetic influence on circulating osteocalcin levels is mediated at least in part through allelic variation in the vitamin D receptor (VDR) gene as detected by restriction fragment length polymorphism (RFLP) analysis (submitted for publication. This study will:- (1) assess the extent to which these common allelic variation in the vitamin D receptor gene predicts response of bone turnover indices to 1,25- dihydroxyvitamin D3 and the observed differences in bone density and bone turnover indices within and between ethnic groups in a large scale Australian community study and selected ethnic groups in the USA and Asia (2) characterize the molecular differences between the two common functionally distinct VDR gene alleles and develop screening methods for these differences (3) examine common allelic differences in steroid hormone receptor genes in relation to bone turnover indices and rates of change of bone density with respect to hormone deficiency and/or excess in postmenopausal women, hypogonadal males receiving testosterone replacement and subjects receiving long-term corticosteroid therapy. This component will extend our vitamin D receptor gene findings for the estrogen, and androgen and glucocorticoid receptor genes. This study will combine powerful molecular biological tools, including restriction fragment length polymorphisms (RFLP), in vitro gene reconstruction and PCR, with our extensive clinical study base and experience in clinical osteoporosis research. The clinical data base includes cohorts of men and women from long term studies in whom we have extensive information on bone turnover and rates of change of bone density extending up to 5 years. This combination has allowed the definition of a genetic effect acting through the vitamin D receptor and provides a unique opportunity to investigate these new area of osteoporosis research in collaboration with several international groups.